Colon cancer remains a daunting problem of near epidemic proportions in the Unites States and in many countries throughout the world. Incidence and mortality rates have changed little despite the availability of validated screening techniques and recent public attention. Accumulating evidence indicates that inherited susceptibility to colon cancer is common and that a number of specific cell signaling and molecular genetic pathways are involved in the pathogenesis of this malignancy. The long-term goals of this project are therefore to decrease the incidence and mortality of colon cancer by identifying genetic risk groups for screening and intervention, and by investigating key mechanistic pathways of colon carcinogenesis to define molecular targets that would be useful for prevention and treatment. A primary focus is the adenomatous polyp, the precursor of colon cancer. Study of this lesion clinically and in the laboratory is emphasized as a method of clarifying the early stages of colon cancer pathogenesis. This program project includes 5 interrelated projects served by 3 core facilities. In project 1, susceptibility and modifying genes that confer moderate but common colon cancer risk will be identified through the study of large kindreds available in the Utah Population Data Base. The phenotype of common familial risk will also be characterized. Project two address mechanisms that give rise to the cellular and tissue effects of COX-2 over-expression in colonic neoplasms. The role of COX-2 as a progression factor in both the genetic and environmental models of carcinogenesis will be examined, and downstream pathways of COX-2 and related arachidonic acid enzymes will be elucidated. Project 3 investigates the provocative findings that failure of colonocyte differentiation in the neoplastic process is a result of reduced retinoic acid production, which in turn is controlled by APC function and a colon specific transcription factor, Cdx2. Project 4 examines the role and regulatory function of casein kinase Ie, a newly identified but likely integral part of the Wnt signaling pathway. Project 5 investigates the mechanisms by which reactive intermediates of electrophylic lipids, elevated in both neoplasms and inflammation, inactivate certain tumor suppressors and other protective pathways and thereby allow the neoplastic process to proceed or accelerate. These studies offer a unique opportunity to identify large population groups for targeted screening and to define genetic and molecular targets that will be useful in intervening in and reversing the pathogenic process of colonic polyps and cancer.